: The opioid use epidemic has not abated despite a recent overall decrease in the number of opioid analgesics prescribed by US providers. The discordance between opioid analgesic prescribing and opioid overdose rates highlight a fundamental gap in our understanding of the pathogenesis of opioid misuse and opioid use disorders after the initiation of prescription opioids for pain. It is important to discern who will transition to persistent opioid use, given its association with the development of misuse and opioid use disorders (OUDs) and subsequent risk for heroin use, drug-related mortality, and overdose. However, concerns about the risk of initiation of opioids must be balanced against their benefits. To address our lack of knowledge on how to improve pain outcomes while decreasing opioid use, we will derive and validate the STAAMP (Support Tool for Assessing Analgesic Medication before Prescribing) predictive model that ultimately aids decision-making on when to initiate prescription opioids or non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute musculoskeletal pain among opioid-nave adult emergency department (ED) patients presenting after a MVC. Based on ED point-of-care information available to the practitioner, the STAAMP tool is intended predict pain outcomes and opioid use 6 weeks after the ED visit. We will use two existing cohorts of ~1900 ED MVC patients to derive the STAAMP model. Next, we will prospectively validate the STAAMP model among 420 opioid-nave adult patients that are discharged from the ED with acute musculoskeletal pain following MVC. Lastly, we will explore the dynamic relationship between pain and persistent opioid use in a causal mediation analysis.